Method for producing medicaments from plant extracts, in a solid form of administration

ABSTRACT

A dry extract is reduced in volume by compacting to produce a solid form of pharmaceutical such as a tablet or capsule containing plant extracts. The particles of compacted matter are subsequently screened to a uniform grain size, masked with titanium dioxide, talc, and highly dispersed silicon dioxide in a first mixing process, and treated with additional adjuvants in two more mixing steps. 
     The masked compacted matter has the flowability required for making tablets and is protected against moisture absorption. The extract portion is a minimum of 65 percent by weight, which allows for producing relatively small tablets that have low disintegration times due to masking.

This invention relates to a method for producing pharmaceuticals in asolid form of application that contain plant extracts, in particular,St. John's wort extract.

The advantage of solid forms of pharmaceuticals such as tablets orcapsules as compared to liquid forms of application is that they act inmore downstream sections of the intestinal duct. This facilitates a morecontrolled release of the active ingredients and therefore bettertherapeutic control. The doctor can exactly dose each individual doseadministered to treat a patient as required. In addition, solidpharmaceuticals are extremely stable and easily packaged, stored andtransported.

An unsatisfactory aspect about administering tablets or capsulescontaining plant extracts, however, is that they are characterized by alarge portion of adjuvants combined with relatively small portions ofpharmaceutically active plant extracts so that their absorption andactive agent concentrations at the absorption site are rather low.Furthermore, these tablets are comparatively large which makes itdifficult for patients to swallow them.

DE 197 00 788 A1 disclosed a pharmaceutical based on St. John's wortextract that can be administered orally in dried form as a powder,granulate, capsule, or tablet. This document, however, does not revealany engineering instructions as to how a tablet that is highly enrichedwith plant extract should be manufactured.

DE 196 39 375 A1 describes a dry mistletoe extract that is to be used asa powder or granulate in a capsule or tablet, or as a liquid. Inparticular, this invention suggests oral administration of a granulatecontaining calcium carbonate or saccharide.

A similar form of application is known from DE 196 27 376 A1 for apharmaceutical based on an artichoke extract.

The pharmaceuticals mentioned above all share the disadvantage that theydo not represent forms of application highly enriched with dried plantextract. This means that multiple tablets or a tablet so big that itcannot be swallowed would have to be administered if the dosage of thepharmaceutical is sufficiently high.

DE 36 16 054 A1 claims a homeopathic pharmaceutical. To produce thispharmaceutical, triturations of pig's bone marrow, pig's articularcartilage, gelatin and harpagophytins as well as an extremely highportion of adjuvants are granulated through a sieve. The granulate iscross-linked with more adjuvants and pressed into tablets. As thisproduct has such a high portion of adjuvants, this method ofmanufacturing tablets from granulate cannot be used for tablets fromplant extracts sized for oral application, which means tablets that areas low in adjuvants and as high in dried extract as possible.

A pharmaceutical preparation of extracts from various drugs known fromDE 33 28 262 C 2 can be administered as a liquid or as a dry extract inthe form of a powder, granulate, tablet, or capsule. In one of itsembodiments, the powdered dry extract is mixed with lactose andmagnesium stearate and pressed into tablets that are later granulated toyield the ready-for-use pharmaceutical preparation. In a secondembodiment, the powdered dry extract is mixed with cellulose andmagnesium stearate and immediately pressed into tablets. Although thispatent describes solid forms of application that have a high portion ofplant extracts, a tablet pressed in this way from a dry extract does notguarantee compliance with the parameters a pharmaceutical calls for,such as disintegration time and moisture protection.

JP 78 13 347 and JP 77 102 4416 each describe the manufacture ofgranulates produced from plant extracts by adding various adjuvantswithout specifically claiming conditions required for the industrialproduction of tablets containing a high portion of dry extract andmeeting other requirements a conventional pharmaceutical would have tomeet.

It is therefore the problem of this invention to propose a method forproducing ready-made pharmaceuticals in a solid form of applicationwhose active ingredient is a plant extract, and thereby to provide agalenically stable, highly effective pharmaceutical containing a largedose of extract in a comparatively small tablet that is easily dissolvedand absorbed at the place of release.

This problem is solved according to the invention by a method comprisingthe characteristics described in claim 1.

In other words, it is the concept of the invention to compact a dryextract into granulate particles screened to a uniform size and to maskthese particles in a mixing process with three layers of titaniumdioxide, talc, and highly dispersed silicon dioxide. These granulateparticles—compacted and masked with other adjuvants as may berequired—are then further processed in the usual way to become tabletsor capsules.

The combination of a compacting step, a screening to uniform grain sizestep, and a masking step as described yields a raw material that hasgood flow characteristics, an extremely high extract content, requiresan accordingly smaller portion of adjuvants, and is therefore suited forthe industrial manufacture of tablets and capsules. As the extractportion in the masked compacted matter is at least 65 percent by weight,a highly effective pharmaceutical based on plant extracts can beprovided in typical tablet size. The adjuvants applied in the definedorder when masking the granulate particles do not conflict with theefficacy of the pharmaceutical as the outer coat of highly dispersesilicon dioxide prevents the granulate particles from melting into oneanother at their outer surfaces so that they disintegrate fast afterintake and unfold their full efficacy.

In the three-step masking process, the titanium dioxide, whichpreferably is applied first, covers all surface areas of the granulateparticles and provides moisture protection for the typically hygroscopicextract. The talc applied subsequently to the titanium dioxide coatfills any remaining spaces of the granulate surface to yield a smoothand continuous surface. Finally, the highly dispersed silicon dioxide asthe outer coat acts as a separating layer between granulate particles ina pressed tablet. The granulate particles masked in this way are alsocharacterized by good flowability, which is advantageous for furtherprocessing.

The subclaims and the subsequent description of an embodiment discloseother characteristics and advantageous improvements of the invention.

The method of the invention for producing tablets with plant extractsshall now be explained in more detail for the use of St. John's wort asan active ingredient for the treatment of depressions.

A liquid extract made of coarsely cut St. John's wort buds andflowertops using an ethanol-water mixture is evaporated to a viscid massand in a step A converted by spray drying into a powdered dry extract towhich specific adjuvants such as maltodextrin and highly dispersedsilicon dioxide are added at a ratio of 9 to 1, amounting to a portionof 10 percent by weight of the dry plant extract. Other dextrins may beused alternatively.

In a step B, this dry extract is mechanically compacted into a granulatewhile adding lactose monohydrate as a binding agent. Alternativeadjuvants such as lactose derivatives, cellulose derivatives, starch,mannitol, and calcium carbonate may be used in this step. A finalscreening process provides compacted matter with a uniform grain sizeand a maximum adjuvant portion of 15 percent by weight.

The still hygroscopic granulate with a homogeneous grain size is maskedin a subsequent first of three mixing processes combined under step Cfirst with titanium dioxide, then with talc, and finally with highlydispersed silicon dioxide to provide the tablets to be produced from thegranulate with moisture protection, good flowability and gooddisintegration properties. The homogeneous grain size of the granulateensures even and thin coating of all particles. In second and thirdmixing processes, the particles are further masked with lactosemonohydrate and carbomethyl cellulose sodium, and then with magnesiumstearate/stearic acid. The adjuvant portion now amounts to a maximum of35 percent by weight. Alternatively, the adjuvants mentioned above canbe used instead of lactose monohydrate, and sodium hydrogencarbonate,calcium carbonate, starch, pectin, magnesium oxide, potassiumbicarbonate and potassium carbonate can be used for sodium carboxymethylcellulose.

The good flow properties of the masked compacted particles make themsuited for immediate processing in a tablet press (step D). The tabletpellets produced in this way are subsequently provided with a coat toprotect them from light, oxygen, and moisture. The portion of dry plantextract is a minimum of 60 percent by weight after this. The tablet thatcan be produced in this way from plant extracts has good disintegrationcharacteristics and facilitates high and accurate dosing of the St.Johns wort extract while being small in size and thus easy to swallow.

The invention is not limited to the embodiment described above. Variousmodifications regarding the dry extract and its production or theadjuvants used are conceivable within the framework of the concept ofthe invention, that is, producing a compactate of equally sizedparticles from dry extract that are subsequently masked with specificadjuvants and can be pressed to tablets with an extract portion between65 and 75 percent by weight.

We claim:
 1. A method for producing pharmaceuticals in a solid form froma liquid St. John's wort extract, the method comprising steps of: a)converting a liquid St. John's wort extract into a dry extract, providedthat at least one adjuvant is added during the conversion of the liquidextract into a dry extract; b) compacting the dry extract into agranulate, provided that at least one substance is added during thecompacting to improve granulation; c) screening the compact granulate toa uniform size; d) coating the compact granulate first with titaniumdioxide, then with talc and then with highly dispersed silicon dioxidein that order; and e) pressing the compact and coated granulate intotablets.
 2. The method according to claim 1 wherein lactose monohydrateis added as an adjuvant during the compacting of the dry extract.
 3. Themethod according to claim 1 further comprising the step of treating thecompact and coated granulate after step d) with at least one adjuvant toform a mixture suitable for forming a tablet.
 4. The method according toclaim 3 wherein the compact and coated granulate is first treated withlactose monohydrate and caboxymethyl cellulose sodium and then treatedwith magnesium stearate and stearic acid.
 5. The method according toclaim 1, 2, 3 or 4 wherein the amount of adjuvant to dry extract doesnot exceed 35 percent by weight.
 6. The method according to claim 1, 2,3 or 4 wherein the amount of adjuvant does not exceed 10 percent byweight during the production of the dry extract, does not exceed 5percent during compacting, and does not exceed 20 percent by weightduring the coating of the compact granulate with the titanium dioxide,talc and silicon dioxide.